Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) is a member of the TNF-receptor superfamily that is preferentially expressed by activated and antigen-experienced T lymphocytes. TNFRSF25 is activated by the TL1A (TNFSF15) ligand, which is rapidly upregulated in antigen presenting cells and in some endothelial cells following Toll-Like Receptor or Fc receptor activation. TNFRSF25 can stimulate NF-kappa B activity, and also can stimulate caspase activation to regulate cell apoptosis (Bodmer et al., Immunity 6(1):79-88, 1997; and Kitson et al., Nature 384(6607):372-375, 1996). Alternative splicing produces multiple distinct isoforms of TNFRSF25, most of which are potentially secreted molecules. Alternative splicing of the TNFRSF25 gene in B and T cells encounters a program change upon T-cell activation, which predominantly produces full-length, membrane bound isoforms, and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation.
Activation of TNFRSF25 is dependent on previous engagement of the T cell receptor. After binding to TL1A, TNFRSF25 signaling increases the sensitivity of T cells to endogenous IL-2, and enhances T cell proliferation. Since activation of TNFRSF25 is T cell receptor dependent, the activity of TNFRSF25 in vivo is specific to T cells that are encountering cognate antigen. At rest, and when there is no underlying autoimmunity, the majority of T cells that regularly encounter cognate antigen are FoxP3+ regulatory T cells. Stimulation of TNFRSF25, in the absence of any other exogenous signals, stimulates highly specific proliferation of FoxP3+ regulatory T cells from a baseline of 8-10% of all CD4+ T cells to 35-40% of all CD4+ T cells, within five days (Schreiber et al., J Clin Invest 120(10):3629-3640, 2010). Therapeutic agonists of TNFRSF25 can be used to stimulate Treg expansion, which can reduce inflammation in experimental models of asthma, allogeneic solid organ transplantation, and ocular keratitis (Schreiber et al., supra; Reddy et al., J Virol 86(19):10606-10620, 2012; and Wolf et al., Transplantation 94(6):569-574, 2012). Similarly, because TNFRSF25 activation is antigen dependent, costimulation of TNFRSF25 together with an autoantigen or with a vaccine antigen can lead to exacerbation of immunopathology or enhanced vaccine-stimulated immunity, respectively (Schreiber et al., J Immunol 189(7):3311-3318, 2010).